The invention relates to medicine, specifically to antiglucocorticoid preparations of a non-steroid nature, i.e. preparations whose chemical structure contains no steran nucleus. The purpose of the invention is to defend somatic mammary cells from the action of glucocorticoid hormones.
The following glucocorticoid-suppressive substances are known to be in use in medicine:
1. Substances which suppress the synthesis of steroid hormones at various stages (inhibitors of enzymes which catalyze various stages of the synthesis of steroid hormones [1]):
a) derivatives of diphenylmethane, e.g. amphenon B (which suppresses the synthesis of steroid hormones at stages 11-.beta.-, 17- and 21- of hydroxylase); PA1 b) derivatives of pyridine (SU-c series), e.g. metirapon (which suppresses synthesis at stage 11-.beta. of hydroxylase); PA1 c) substituted .alpha.,.alpha.-glutaramides, e.g. aminoglutetimide (which impedes the synthesis of pregnenolon from cholesterine through suppression of 20-.alpha.-hydroxylase and C20, C-22-liase; PA1 d) steroid substances, PA1 a) steroid substances, PA1 b) non-steroid substances [2], e.g. drotaverina hydrochloride (a derivative of isoquinoline-1-(3.4-dietoxibene zilidene)-6.7-dietoxy-1,2,3,4-tetrahydrizoquinoline) or acetylsalicic acid [5]. PA1 it is effective only in high doses (400 mg/day); PA1 its structure contains a steran nucleus; PA1 it affects receptors of sexual steroids, progestins and mineralocorticoids. PA1 1) ANAESTHETIZING PROPERTIES, leading to the use of such pheromones as anaesthetics [11]; PA1 2) ABILITY TO SUPPRESS BACTERIA [12] AND VIRUSES [13,14], leading to their use for this purpose in medicine and biology; PA1 3) ABILITY TO INDUCE LYSIS OF ERYTHROCYTES [15], leading to their use as inductors of lysis of erythrocytes [15].
e.g. trilostan (3.beta.-substituted steroid-3.beta.-hydroxy-5-androsten-17-one), which suppresses 3.beta.-desoxysteroidhydrogenase-5.4-isomerase [4]. PA2 e.g. mifepriston (11.beta.-substituted steroid derivative-11.beta.-(4 dimethyl-aminophenyl)-17.beta.-hydroxy-17.alpha.-(prop-1-inyll)-estra4.9di en-3-one), which acts on receptors of glucocorticoid hormones to form a complex incapable of initiating mechanisms of the glucocorticoid effect [3];
2. Substances which suppress the interaction of glucocorticoid hormones with hormone receptors:
The above-named preparations have a determinate antiglucocorticoid effect when taken as an ingredient in various medicines.
It is also known that the above-listed preparations have a number of significant drawbacks:
1. Preparations which inhibit the synthesis of glucocorticoids also inhibit, depending upon the target enzymes, the synthesis of other steroid hormones (i.e. sexual steroids and/or mineralocorticoids) and elicit an accumulation of the predecessor substrates of inhibited enzymes, which substrates also display hormonal activity.
2. The level of specificity of effect of preparations in the second group is very low, i.e. in addition to an antiglucocorticoid effect, they also have other steroidal antihormonal effects as well.
3. All steroid substances in one way or another upset the balance of steroids in the human organism. Such substances may form metabolites possessing active characteristics different to those of the substance initially administered to the patient.
Of the above-listed preparations Mifepriston (RU 486), a medicine containing a steran nucleus, is the most free of the above-named defects, is the most specific in its ability to block glucocorticoid receptors, and is closest in its pharmacological action to the group of medicines which are the subject of the present application. Mifepriston is described in greater detail in, for example, [3] and [6]. Hereafter in the present application Mifepriston will be used as the most frequent comparison for the effectiveness of the antiglucocorticoid medicine which is the subject of this application (hereinafter called `the proposed drug`). Together with its great advantages, Mifepriston, like other analogues, possesses a number of weak points:
Also known are insect pheromones, i.e. substances produced and excreted into the environment by insects and having a specific smell that acts upon specific (pheromone) receptors in sensitive members of the same insect type, eliciting in the latter a typical behavioral reaction or process, e.g. attraction of insects of the opposite sex to a meeting site, preparations for fertilization etc. [8].
One group of pheromones comprises, specifically, long-chain aliphatic unsaturated alcohols, ethers and acetates containing in a linear hydrocarbon chain between 10 and 21 carbon atoms. Pheromones of this group are used as domestic and agricultural insecticides [7,8].
The specific physical and chemical characteristics of the above-named pheromones and their synthetic analogues and derivatives (specifically, the pronounced hydrophobic property of the long-chain hydrocarbon structure) give them the ability easily to dissolve in fats and to incorporate themselves into biological membranes, altering the physical and mechanical properties (liquidity, penetrability) of such membranes. The latter ability allows them to be used as an ingredient in preparations intended to enhance the transcutaneous penetrability of membranes [10].
The hydrophobic tendency of the given group of pheromones explains the use currently made in medicine and biology of the biological properties of such pheromones. Such properties are:
Obviously, the above-described known properties of the given group of pheromones and of their synthetic analogues and derivatives, and the cosmetic, agricultural and biological uses of such pheromones, analogues and derivatives have no relation to glucocorticoid activity (detailed proof of this statement will be given below); this explains why none of the experts known to us has ever had an interest in the above-named substances from the point of view of using them to produce an antiglucocorticoid effect.